This is a competing continuation application of R-01DK51081. In the past, it has explored the human physiology of parathyroid hormone-related protein (PTHrP). In its most recent cycles, it has also focused on exploring the therapeutic potential of PTHrP as an anabolic skeletal agent for the treatment of osteoporosis. Data in the prior versions have demonstrated that PTHrP is at least as efficacious in humans as the current gold standard for the anabolic treatment of osteoporosis: parathyroid hormone or PTH(1-34). In addition, in the prior round of funding, we have defined the complete therapeutic window of PTHrP(1-36) in healthy young adults as well as in postmenopausal women: these studies demonstrate that doses of PTHrP higher than those previously employed appear safe as well as effective. These findings suggest that higher doses of PTHrP may be even more efficacious than those prior studied. Further, in addition to potential superior efficacy, PTHrP appears to have a superior safety and tolerability profile, with no hypercalcemia, nausea, muscle cramps or other adverse effects at therapeutic doses. Finally, in contrast to PTH which is a mixed anabolic and catabolic agent, PTHrP appears to be a pure anabolic agent. Collectively, these studies mandate a definitive head-to-head comparator trial of PTH(1-34) vs. PTHrP(1-36) in the treatment of postmenopausal osteoporosis. This is the single Specific Aim of this study: To perform a direct, head-to-head, direct comparator, randomized, controlled clinical trial of PTHrP(1-36) vs. PTH(1-34) for the treatment of postmenopausal osteoporosis, with both safety/tolerability and efficacy endpoints. PUBLIC HEALTH RELEVANCE: Osteoporosis is a major cause of fracture, pain, disability, and other morbidities as well as mortality in postmenopausal women, aging men, and patients treated with glucocorticoids. Anti-resorptive therapies are partially effective, and anabolic therapies are even more effective. The current gold standard anabolic agent is PTH(1-34), but its safety and efficacy is limited by nausea, muscle cramps, hypercalcemia and other adverse effects. Reports published from earlier versions of this grant suggest that PTHrP may have superior safety and tolerability, and also may confer efficacy advantages over PTH. The purpose of this project is to directly compare, for the first time, PTH and PTHrP in an efficacy and safety/tolerability study.